Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups. Type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.
The current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.
Over time, almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.
Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion (i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose); low primary and secondary failure rates; and preservation of islet cell function.
INS-1 cells are a model for islet beta-cell insulin secretion. When maintained in the presence of beta-mercaptoethanol, these cells retain many of the characteristics of islet beta-cells in situ. The cells secrete insulin in response to physiologically relevant glucose concentrations with an EC50 of 6 mM glucose (Hohmeier, et al., Diabetes 49:424, 2002). These cells also secrete insulin in response to multiple known secretagogues, including agents that elevate intracellular cyclic AMP, nutrients other than glucose, and potassium chloride. This characteristic of INS-1 cells further demonstrates that the cells retain many of the signaling pathways that are involved in the insulin secretory response, and as such are suitable for identifying compounds that affect these pathways. INS-1 cells are therefore useful tools for identifying compounds that stimulate insulin secretion in the presence of glucose, and such compounds are useful in the treatment of diabetes and related disorders.